The intracellular enzyme p38 MAPKα has been best characterized as a regulator of pro-inflammatory cytokines (IL-1β and TNFα) production from macrophages and microglia, and is considered a therapeutic target in Alzheimer's disease (Munoz, 2010); the primary rationale being the reduction of inflammatory mediators from microglia and their impact downstream of Aβ: excitotoxity, synaptic dysfunction, and tau phosphorylation. IL-1β-p38 MAPKα may also directly modulate memory formation and cognitive function through effects on long-term potentiation/depression (MacAfoose, 2009; Barrientos, 2012). However, no p38 MAPKα anatagonists have been developed for AD due to previous unavailability of blood-brain-barrier (BBB) penetrant compounds. Given their known action on pro-inflammatory cytokine production, P38 MAPK inhibitors otherwise have been evaluated in a wide range of non-CNS diseases (rheumatoid arthritis, inflammatory bowel disease, COPD) as anti-inflammatory agents. Thus, there remains an important unmet need to develop p38 MAPKα anatgonists that penetrate the BBB as treatments of AD and other neurological conditions.